EP2955174B1 - Dérivé de l'homosérine lactone, procédé de préparation et application associés - Google Patents

Dérivé de l'homosérine lactone, procédé de préparation et application associés Download PDF

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Publication number
EP2955174B1
EP2955174B1 EP13874809.0A EP13874809A EP2955174B1 EP 2955174 B1 EP2955174 B1 EP 2955174B1 EP 13874809 A EP13874809 A EP 13874809A EP 2955174 B1 EP2955174 B1 EP 2955174B1
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Prior art keywords
phenyl
compound
oxotetrahydrofuran
sulfamoyl
benzamide
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EP2955174A4 (fr
EP2955174A1 (fr
Inventor
Song Li
Junhai Xiao
Mingming ZHAO
Wu Zhong
Lili Wang
Zhibing Zheng
Yunde Xie
Xingzhou Li
Guoming Zhao
Xinbo Zhou
Xiaokui Wang
Wei Chen
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention belongs to a medical and chemical engineering field, specifically relates to design and synthesis as well as medical use of a new quorum-sensing regulator.
  • Auto inducers Bacteria communicate with each other by small auto-generated signal molecules, which are termed as auto inducers (Als in brief). During the growth of bacterial quorum, these auto inducers are produced continuously and are subsequently secreted in the extracellular environment. When the concentration of the signal molecules reaches a threshold value, the expression of relevant genes in bacteria is initated to adapt to the environmental changes.
  • Such a regulatory system is termed as bacterial quorum sensing (QS) signal systems.
  • QS enables unicellular bacteria to imitate multicellular organisms to accomplish some behaviors that can not be accomplished when they are unicellular individuals.
  • the autoinduction signal molecules When the population density of bacteria increases gradually and reaches a threshold value, the autoinduction signal molecules will be permeated into cells and bind to transcriptional regulatory proteins to form a transcriptional regulatory protein-signal molecule polymer, which can bind to a specific DNA sequence of the signal molecule in chromosome to enable the expression of target genes including the synthetic gene of the signal molecule, also resulting in the production of more signal molecules.
  • a transcriptional regulatory protein-signal molecule polymer Such communication and transduction of information among bacteria has been proposed for a long time. However, systematic research is only conducted in the recent 10 years. Such a phenomenon has been demonstrated to be present in many bacteria. For example, chromobacterium violaceum has the same mechanism as V.fischeri, and can produce C6-HSL as an auto induction molecule, the receptor protein of which is CviR.
  • Bacterial quorum sensing enables the regulation of expression of some relevant genes in a population of bacteria, such as regulation of generation of antibiotics, bioluminescence, regulation of nitrogen-fixing gene, conjugal transfer of Ti plasmid, expression of virulent gene, pigment generation, bacterial swarming, formation of biofilms, and the like.
  • bacterial quorum-sensing regulators including agonists or inhibitors
  • Bacterial quorum-sensing regulators do not interfere with normal physiolocial functions of cells in vivo , and thus are regarded as new direction for the development of antibacterials.
  • Bacterial quorum-sensing inhibitors can be used in combination with antibiotics to enhance sensitivity of pathogenic bacteria to antibiotics, and can be used to treat a disease (including, but not limited to peritonitis,cholecystitis,cystitis,diarrhea, endocarditis, gastroenteritis, pyothorax, sepsis and other various diseases) caused by a Gram-negative bacterium including, but not limited to E.
  • Bacillus proteus Bacillus dysenteriaei, Bacillus pneumoniae , Brucella , Haemophilus influenzae, Hemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter , Yersinia , legionella pneumophila , Bordetella pertussis , Bordetella parapertussis , Shigella spp ., Pasteurella , Vibrio cholerae , and Vibrio Parahemolyticus, particularly, to treat a disease caused by drug-resistant Gram-negative bacteria not sensitive to current antibiotics.
  • the purpose of the invention is to synthesize new bacterial quorum-sensing regulator, for use in the treatment of a disease caused by a Gram-negative bacterium, particularly a disease caused by drug-resistant Gram-negative bacteria.
  • the present invention provides a derivative of homoserine lactone represented by formula I, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof,
  • R is C1-9 linear or branched alkyl, or phenyl
  • said alkyl or phenyl is optionally mono-substituted or multi-substituted by a substituent selected from the group consisting of: phenyl, C1-5 linear or branched alkyl, C1-5 linear or branched alkyl mono-substituted or multi-substituted by halogen, cyano, trifluoromethyl, hydroxyl, nitro, C1-5 alkoxyl, C1-5 alkoxyl mono-substituted or multi-substituted by halogen.
  • Related homoserine lactone derivatives regulating quorum sensing are disclosed in KR20080046434 .
  • R is C1-9 linear or branched alkyl, or phenyl, said alkyl or phenyl is optionally mono-substituted or multi-substituted by a substituent selected from the group consisting of: phenyl, C1-4 linear or branched alkyl, C1-4 linear or branched alkyl mono-substituted or multisubstituted by halogen, halogen, cyano, trifluoromethyl, hydroxyl, nitro, C1-4 alkoxyl, C1-4 alkoxyl mono-substituted or multi-substituted by halogen.
  • R is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl, nitrophenyl, cyanophenyl, methylphenyl, ethylphenyl, benzyl, trifluoromethylphenyl, methoxyphenyl, ethoxyphenyl, or halogenated methylphenyl.
  • the derivative of homoserine lactone represented by formula I, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof according to the first aspect of the present invention is selected from the group consisting of:
  • the derivative of homoserine lactone represented by formula I, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof according to the first aspect of the present invention is selected from the following group consisting of:
  • the derivative of homoserine lactone represented by formula I, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof according to the first aspect of the present invention is selected from the following group consisting of:
  • the present invention provides a method for preparing the derivative of homoserine lactone represented by formula I according to the first aspect of the presnet invention, comprising the following steps of:reacting an intermediate represented by formula 3 with acyl chloride represented by RCOCI, to prepare the derivative of homoserine lactone represented by formula I, wherein R is defined as the first aspect of the present invention.
  • the intermediate represeanted by formula 3 is obtained by reacting acetamino-benzenesulfonyl chloride with homoserine lactone hydrobromide.
  • reaction scheme in the method according to the second aspect of the present invention, the reaction scheme is shown as follow: wherein R is defined as the first aspect of the present invention.
  • the present invention provides a pharmaceutical composition, comprising the derivative of homoserine lactone represented by formula I, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof according to the first aspect of the present invention, and optionally one or more pharmaceutically acceptable carriers or excipients.
  • the derivative of homoserine lactone represented by formula I, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof according to the first aspect of the present invention, as a bacterial quorum sensing regulator, may be used in combination with antibiotics to enhance sensitivity of pathogenic bacteria to antibiotics.
  • the pharmaceutical composition according to the third aspect of the invention may further comprise one or more antibiotics.
  • the present invention provides use of the derivative of homoserine lactone represented by formula I, a racemate or optical isomer a pharmaceutically acceptable salt, a solvate or a hydrate thereof according to the first aspect ov the present invention, in the preparation of a medicament as a bacterial quorum sensing regulator.
  • the present invention provides use of the pharmaceutical composition according to the third aspect of the present invention in the preparation of a medicament as a bacterial quorum sensing regulator.
  • said bacterial quorum sensing regulator may be a bacterial quorum sensing agonist, or a bacterial quorum sensing inhibitor.
  • the derivative of homoserine lactone represented by formula I selected from the following compounds, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof may be used in the preparation a medicament as a bacterial quorum sensing agonist, (S)-4-bromo-N-(4-(N-(2-oxotetrahydrofuran-3-yl)sulfamoyl)phenyl)benzamide (Compound12), and (S)-4-(chloromethyl)-N-(4-(N-(2-oxotetrahydrofuran-3-yl)sulfamoyl)phenyl)benza mide(Compound15).
  • the derivative of homoserine lactone represented by formula I selected from the following compounds, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof may be used in preparation a medicament as a bacterial quorum sensing inhibitor, (S)-N-(4-(N-(2-oxotetrahydrofuran-3-yl)sulfamoyl)phenyl)propanamide (Compound 1), (S)-N-(4-(N-(2-oxotetrahydrofuran-3-yl)sulfamoyl)phenyl)butyrylamide (Compound 2), (S)-N-(4-(N-(2-oxotetrahydrofuran-3-yl)sulfamoyl)phenyl)pentanamide (Compound 3), (S)-N-(4-(N-(2-oxotetrahydrofuran
  • the derivative of homoserine lactone represented by formula I, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof according to the first aspect of the present invention can inhibit or agonize bacterial quorum sensing, does not interfere with normal physiological functions of cells in vivo, and thus is regarded as the new direction for the development of antibacterials.
  • the derivative as quorum sensing inhibitor can be used in combination with antibiotics, to enhance sensitivity of pathogenic bacterium to antibiotics, and can be used to treat a disease or infection (including, but not limited to peritonitis, cholecystitis, cystitis, diarrhea, endocarditis, gastroenteritis, pyothorax, sepsis and other various deseases) caused by a Gram-negative bacterium including, but not limited to E.
  • a disease or infection including, but not limited to peritonitis, cholecystitis, cystitis, diarrhea, endocarditis, gastroenteritis, pyothorax, sepsis and other various deseases
  • the present invention provides use of the derivative of homoserine lactone represented by formula I, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof according to the aspect of the present invention, in the preparation of a medicament for prevention and/or treatment of a decease caused by a bacterial infection.
  • the present invention provides use of the pharmaceutical composition according to the third aspect of the present invention in the preparation of a medicament for prevention and/or treatment of a decease caused by bacterial quorum sensing.
  • said disease caused by bacterial quorum sensing includes, but is not limited to an infection or a disease (including, but not limited to peritonitis, cholecystitis, cystitis, diarrhea, endocarditis, gastroenteritis, pyothorax, sepsis and other various diseases,) caused by a Gram-negative bacterium such as E.
  • a disease including, but not limited to peritonitis, cholecystitis, cystitis, diarrhea, endocarditis, gastroenteritis, pyothorax, sepsis and other various diseases, caused by a Gram-negative bacterium such as E.
  • the present invention provides use of the derivative of homoserine lactone represented by formula I, a racemate or optical isomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof according to the first aspect of the present invention as a tool drug for studying bacterial quorum sensing regulation.
  • alkyl has the general meangings well known in the art, and generally includes linear or branched alkyl.
  • the "alkyl” described in the invention may be C1-C12 alkyl, C1-C10 alkyl, C1-C6 alkyl or C1-C4 alkyl.
  • the C1-C12 alkyl, C1-C10 alkyl, C1-C6 alkyl or C1-C4 alkyl refers to alkyl containing 1 to 12, 1 to 10,1 to 6, or 1 to 4 (including end values) carbon atoms, respectively.
  • The"alkyl" described in the invention includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • halogen has the general meanings well known in the art, and generally includes F, Cl, Br, I, as well as their isotopes, and are preferably F, Cl and Br in the invention.
  • nitrile group trifluoromethyl, trifluoromethoxyl, hydroxyl, nitro, alkoxyl, and cyano.
  • racemate or “optical isomer” have the general meanings well known in the art.
  • the above compounds of Formula I can be prepared by the following typical and exemplified method, comprising the steps of:
  • the invention synthesizes a class of new bacterial quorum-sensing regulators represented by Formula I, which do not interfere with normal physiological functions of cells in vivo, and thus are regarded as new direction for the development of antibacterials, wherein the bacterial quorum-sensing inhibitors can be used in combination with antibiotics, to treat an infection or a disease (including, but not limited to peritonitis, cholecystitis, cystitis, diarrhea, endocarditis, gastroenteritis, pyothorax, sepsis and other various diseases) caused by a Gram-negative bacterium including, but not limited to E.
  • a disease including, but not limited to peritonitis, cholecystitis, cystitis, diarrhea, endocarditis, gastroenteritis, pyothorax, sepsis and other various diseases
  • Bacillus proteus Bacillus dysenteriae
  • Bacillus pneumoniae Brucella
  • Haemophilus influenzae Hemophilus parainfluenzae
  • Moraxella catarrhalis Acinetobacter, Yersinia, legionella pneumophila, Bordetella pertussis, Bordetella parapertussis , Shigella spp ., Pasteurella , Vibrio cholerae , and Vibrio Parahemolyticus , particularly, to treat a disease caused by drug-resistant Gram-negative bacteria not sensitive to current antibiotics.
  • the invention describes the materials and experimental methods used in the experiments generally and/or in detail. Although many materials and methods used to achieve the purpose of the invention are well known in the art, the invention still describes them as detailedly as possible. A person skilled in the art knows that unless otherwise specified, the materials and methods used in the invention are well known in the art.
  • the melting points of the compounds were measured by YRT-3 type melting point apparatus, wherein the temperature was not calibrated.
  • the specific rotatory power was measured by Polaar 3005 type Accuracy Automatic Polarimeter from OA Company.
  • 1 H-NMR spectra were measured by Bruker ARX 400 type NMR spectrometer.
  • FAB mass spectra were measured by Zabspect High Resolution mass spectrometer.
  • D-methionine was used as raw materials to synthesize (D) -4- amino -N-(2-oxotetrahydrofuran-3-yl) benzenesulfonamide by reference to the synthesis method of intermediates, 2-chlorobenzoyl chloride was used as raw materials, and operations were performed as they were in Example 1, to getwhite solid product (compound 29).
  • the activity of the bacterial quorum-sensing regulators according to the invention may be measured by the following methods.
  • the wells of a 12-well plate were marked as initial concentration, 2, 4, 8, 16, 32, 64, 128, 256, DMSO group, and a blank control group from left to right and from up to bottom, respectively.
  • 2.2 The monoclonal C . violaceum CV026 grew on LB solid plate was cultured to exponational phase in a 5ml fresh LB liquid culture medium, 50 ⁇ l was then taken for seeding in a 5ml LB culture medium, and was cultured until the optical density OD value was about 1.0 at 585nm; the culture was then mixed well with LB culture medium at a ratio of 1: 9 by volume (with OD of about 0.15), and was added to a 12-well plate in an amount of 2ml/well.
  • the compounds prelimitarily screened to have quorum sensing inhibitory activity were dissolved respectively in DMSO (at a concentration of 0.065M), and then 10 ⁇ l was taken into 10 ⁇ l DMSO solution to achieve the purpose of 2-fold dilution, and so on.
  • Each compound was gradiently diluted to a highest fold of 256 (gradient dilution of 2, 4, 8, 16, 32, 64, 128, 256 fold).
  • 15 ⁇ l 1000-fold diluted inducer C 6 -HSL (initial concentration of 0.125M) and 8 ⁇ l compound solution at each diluted gradient was added; to DMSO control group, 8 ⁇ l DMSO was added; to a blank control group, 8 ⁇ l LB culture medium was added.
  • Table 1 IC 50 value ( ⁇ M) of compounds having bacterial quorum sensing inhibitory activity Compound No. IC 50 Compound No. IC 50 4 29.00 ⁇ 2.41 9 17.25 ⁇ 2.60 17 14.72 ⁇ 2.58 23 7.79 ⁇ 2.68 24 1.64 ⁇ 0.27 27 4.91 ⁇ 0.97 28 1.66 ⁇ 0.33
  • the invention synthesizes a class of new bacterial quorum-sensing regulators represented by Formula I, which do not interfere with normal physiological functions of cells in vivo, and thus are regarded as new direction for the development of antibacterials, wherein the bacterial quorum-sensing inhibitors can be used in combination with antibiotics, to treat an infection or a disease (including, but not limited to peritonitis, cholecystitis, cystitis, diarrhea, endocarditis, gastroenteritis, pyothorax, sepsis and other various diseases) caused by a Gram-negative bacterium including, but not limited to E.
  • a disease including, but not limited to peritonitis, cholecystitis, cystitis, diarrhea, endocarditis, gastroenteritis, pyothorax, sepsis and other various diseases
  • Bacillus proteus Bacillus dysenteriae
  • Bacillus pneumoniae Brucella
  • Haemophilus influenzae Hemophilus parainfluenzae
  • Moraxella catarrhalis Acinetobacter, Yersinia, legionella pneumophila, Bordetella pertussis, Bordetella parapertussis , Shigella spp ., Pasteurella , Vibrio cholerae , and Vibrio Parahemolyticus, particularly, a disease caused by drug-resistant Gram-negative bacteria not sensitive to current antibiotics.

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Claims (15)

  1. Dérivé d'homosérine lactone représenté par la formule I, un racémate ou un isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci,
    Figure imgb0052
     dans lequel
    R est un groupe alkyle en C1-9 linéaire ou ramifié, ou phényle, ledit groupe alkyle ou phényle est facultativement mono-substitué ou multi-substitué par un substituant sélectionné dans le groupe constitué de : un groupe phényle, un groupe alkyle en C1-5 linéaire ou ramifié, un groupe alkyle en C1-5 linéaire ou ramifié mono-substitué ou multi-substitué par un atome d'halogène, un groupe cyano, un groupe trifluorométhyle, un groupe hydroxyle, un groupe nitro, un groupe alcoxyle en C1-5, un groupe alcoxyle en C1-5 mono-substitué ou multi-substitué par un atome d'halogène.
  2. Dérivé d'homosérine lactone représenté par la formule I, un racémate ou un isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci selon la revendication 1, dans lequel R est un groupe alkyle en C1-9 linéaire ou ramifié, ou phényle, ledit groupe alkyle ou phényle est facultativement mono-substitué ou multi-substitué par un substituant sélectionné dans le groupe constitué de : un groupe phényle, un groupe alkyle en C1-4 linéaire ou ramifié, un groupe alkyle en C1-4 linéaire ou ramifié mono-substitué ou multi-substitué par un atome d'halogène, un groupe cyano, un groupe trifluorométhyle, un groupe hydroxyle, un groupe nitro, un groupe alcoxyle en C1-4, un groupe alcoxy en C1-4 mono-substitué ou multi-substitué par un atome d'halogène.
  3. Dérivé d'homosérine lactone représenté par la formule I, un racémate ou un isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci selon la revendication 1, dans lequel R est un groupe méthyle, éthyle, n-propyle, isopropyle, n-butyle, sec-butyle, tert-butyle, pentyle, hexyle, heptyle, octyle, nonyle, phényle, chlorophényle, bromophényle, fluorophényle, nitrophényle, cyanophényle, méthylphényle, éthylphényle, benzyle, trifluorométhylphényle, méthoxyphényle, éthoxyphényle, ou méthylphényle halogéné.
  4. Dérivé d'homosérine lactone représenté par la formule I, un racémate ou un isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci selon la revendication 1, sélectionné dans le groupe suivant constitué des :
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)propanamide (composé 1),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)butyrylamide (composé 2),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)pentanamide (composé 3),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)hexanamide (composé 4),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)heptanamide (composé 5),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)octanamide (composé 6),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)pélargonamide (composé 7),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)décanamide (composé 8),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 9),
    (S)-4-méthyl-N-(4-(N-(2-oxotétrahydrofuran-3-yl) sulfamoyl)phényl)benzamide (composé 10),
    (S)-4-éthyl-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 11),
    (S)-4-bromo-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 12),
    (S)-4-propyl-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 13),
    (S)-4-chloro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 14),
    (S)-4-(chlorométhyl)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 15),
    (S)-4-(tert-butyl)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 16),
    (S)-4-fluoro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 17),
    (S)-4-cyano-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 18),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)phénylacetamide (composé 19),
    (S)-3-méthyl-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 20),
    (S)-4-méthoxyl-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 21),
    (S)-3-chloro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 22),
    (S)-3-fluoro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 23),
    (S)-2-fluoro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 24),
    (S)-2-éthyoxyl-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 25),
    (S)-4-nitryl-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 26),
    (S)-2-trifluorométhyl-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 27),
    (S)-2-chloro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 28), et
    (D)-2-fluoro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 29).
  5. Dérivé d'homosérine lactone représenté par la formule I, un racémate ou un isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci selon la revendication 1, sélectionné dans le groupe suivant constitué des :
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)propanamide (composé 1),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)butyrylamide (composé 2),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)pentanamide (composé 3),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)hexanamide (composé 4),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)heptanamide (composé 5),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)octanamide (composé 6),
    (S)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 9),
    (S)-4-bromo-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 12),
    (S)-4-chloro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 14),
    (S)-4-(tert-butyl)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 16),
    (S)-4-fluoro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 17),
    (S)-3-méthyl-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 20),
    (S)-3-chloro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 22),
    (S)-3-fluoro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 23),
    (S)-2-fluoro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 24),
    (S)-2-trifluorométhyl-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 27), et
    (S)-2-chloro-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 28).
  6. Dérivé d'homosérine lactone représenté par la formule I, un racémate ou un isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci selon la revendication 1, sélectionné dans le groupe suivant constitué des :
    (S)-4-bromo-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 12), et
    (S)-4-(chlorométhyl)-N-(4-(N-(2-oxotétrahydrofuran-3-yl)sulfamoyl)phényl)benzamide (composé 15).
  7. Procédé de préparation du dérivé d'homosérine lactone représenté par la formule I selon l'une quelconque des revendications 1 à 6, comprenant les étapes suivantes : mise en réaction d'un intermédiaire représenté par la formule 3 avec un chlorure d'acyle représenté par RCOCl, pour préparer le dérivé d'homosérine lactone représenté par la formule I,
    Figure imgb0053
     dans lequel R est tel que défini dans la revendication 1.
  8. Procédé selon la revendication 7, dans lequel l'intermédiaire représenté par la formule 3 peut être obtenu par mise en réaction de chlorure d'acétaminobenzènesulfonyle avec du bromhydrate d'homosérine lactone.
  9. Composition pharmaceutique, comprenant le dérivé d'homosérine lactone représenté par la formule I, le racémate ou l'isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci selon l'une quelconque des revendications 1 à 6, et facultativement un ou plusieurs véhicules ou excipients pharmaceutiquement acceptables.
  10. Composition pharmaceutique selon la revendication 9, dans laquelle la composition pharmaceutique peut en outre comprendre un ou plusieurs antibiotiques.
  11. Composition pharmaceutique selon la revendication 9 ou le dérivé d'homosérine lactone représenté par la formule I, un racémate ou un isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci selon l'une quelconque des revendications 1 à 6, pour son utilisation dans la prévention et/ou le traitement d'une maladie provoquée par une infection bactérienne.
  12. Composition pharmaceutique pour son utilisation selon la revendication 11, dans laquelle ladite maladie provoquée par une infection bactérienne est sélectionnée dans un groupe constitué de la péritonite, de la cholécystite, de la cystite, de la diarrhée, de l'endocardite, de la gastroentérite, du pyothorax et de la sepsie provoqués par une bactérie Gram négatif.
  13. Dérivé d'homosérine lactone représenté par la formule I, un racémate ou un isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci selon la revendication 5, qui est un inhibiteur de la détection du quorum bactérien.
  14. Dérivé d'homosérine lactone représenté par la formule I, un racémate ou un isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci selon la revendication 6, qui est un agoniste de la détection du quorum bactérien.
  15. Dérivé d'homosérine lactone représenté par la formule I, un racémate ou un isomère optique, un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci selon l'une quelconque des revendications 1 à 6, qui est un régulateur de la détection du quorum bactérien.
EP13874809.0A 2013-02-08 2013-12-10 Dérivé de l'homosérine lactone, procédé de préparation et application associés Not-in-force EP2955174B1 (fr)

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US9630939B2 (en) 2017-04-25
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